This project expands on earlier accomplishments targeting common RAS mutations with off-the-shelf T-cell receptors (TCR) and taking such reagents into clinical trials. It will now try to expand not only the anti-RAS repertoire of TCRs, but also develop similar reagents against other commonly and consistently mutated oncogenes. In collaboration with Dr. Guha's laboratory, a major effort will be to determine which mutations are correctly processed and presented on MHC molecules, and which MHC molecules are doing the presentation. Then T-cells from patients with those MHC alleles and appropriately mutated cancers will be screened for T-cell responses, and vigorous efforts to immunize HLA-transgenic mice will be pursued.